Insulin-like growth factor-1 is a negative modulator of glucagon secretion

Abstract

Glucagon secretion involves a combination of paracrine, autocrine, hormonal, and autonomic neural mechanisms. Type 2 diabetes often presents impaired glucagon suppression by insulin and glucose. Insulin-like growth factor-I (IGF-1) has elevated homology with insulin, and regulates pancreatic β-cells insulin secretion. Insulin and IGF-1 receptors share considerable structure homology and function. We hypothesized the existence of a mechanism linking the inhibition of α-cells glucagon secretion to IGF-1. Herein, we evaluated the association between plasma IGF-1 and glucagon levels in 116 nondiabetic adults. After adjusting for age gender and BMI, fasting glucagon levels were positively correlated with 2-h post-load glycaemia, HOMA index and fasting insulin, and were negatively correlated with IGF-1 levels. In a multivariable regression, the variables independently associated to fasting glucagon were circulating IGF-1 levels, HOMA index and BMI, explaining 20.7% variation. To unravel the molecular mechanisms beneath IGF-1 and glucagon association, we investigated whether IGF-1 directly modulates glucagon expression and secretion in an in vitro model of α-cells. Our data showed that IGF-1 inhibits the ability of low glucose concentration to stimulate glucagon expression and secretion via activation of the phosphatidylinositol-3-kinase/Akt/FoxO1 pathway.Collectively, our results suggest a new regulatory role of IGF-1 on α-cells biological function.

Does obesity cause type 2 diabetes mellitus (T2DM)? Or is it the opposite?

“…The first step of β-cell failure and IGT occurs when postprandial GLP-1 levels begin to decline. 39 Prospective studies in human and non-human primates have conclusively demonstrated that insulin resistance and hyperinsulinemia precede the development of IGT and that IGT represents the forerunner of T2DM.…”

“…GLP‐1 is secreted from L cells in the intestinal ileum. GLP‐1 increases glucose transporter 2 expression in pancreatic β‐cells which increases β‐cell sensitivity to glucose for increased insulin secretion, while also restricting glucagon release from the α‐cells and reducing hepatic glucose production. The first step of β‐cell failure and IGT occurs when postprandial GLP‐1 levels begin to decline .…”

“…GLP‐1 increases glucose transporter 2 expression in pancreatic β‐cells which increases β‐cell sensitivity to glucose for increased insulin secretion, while also restricting glucagon release from the α‐cells and reducing hepatic glucose production. The first step of β‐cell failure and IGT occurs when postprandial GLP‐1 levels begin to decline . Prospective studies in human and non‐human primates have conclusively demonstrated that insulin resistance and hyperinsulinemia precede the development of IGT and that IGT represents the forerunner of T2DM.…”

The GLP-1 response to glucose does not mediate beta and alpha cell dysfunction in Hispanics with abnormal glucose metabolism

“…It has been recently shown that Insulin-like growth factor-1 (IGF-1) may play a regulatory role in glucagon secretion in Caucasian subjects without diabetes [28] . The impaired glucagon suppression index seen in our abnormal glucose tolerance group thus could be mediated by an effect of altered IGF-1 concentrations in the alpha cells.…”

Islet macrophages shift to a reparative state following pancreatic beta-cell death and are a major source of islet IGF-1

“…This finding suggests that macrophage-derived IGF-1 is important in limiting beta-cell functional damage post-STZ. While it was beyond the scope of this study to determine the cell-specific actions of macrophage-derived IGF-1, effects on insulin secretion and glucose homeostasis may be due to direct effects of IGF-1 on beta cells (Kulkarni et al, 2002, Dheen et al, 1996, or indirect effects on alpha-cell glucagon secretion (Mancuso et al, 2017), or on other islet cell types to limit tissue inflammation (Han et al, 2016).…”